Guo Xiaoli, Zhang Wei, Ren Jing, Chen Yujiao, Wang Jingyu, Zhu Chendi, Zhang Yanlin, Gao Ai
Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China.
Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing 100069, PR China.
Toxicol Lett. 2020 Oct 10;332:74-81. doi: 10.1016/j.toxlet.2020.07.004. Epub 2020 Jul 6.
Long-term exposure to benzene is associated with adverse health effects such as leukemia. Abnormal cell cycle progression has been reported participating in tumorigenesis. Our previous study found that lncRNA-OBFC2A was involved in benzene toxicity through regulating cell proliferation. However, the function of lncRNA-OBFC2A in the regulation of cell cycle remains obscure and the precise mechanisms need to be explored. In vitro study, results showed that benzene metabolic, 1,4-Benzoquinone (1,4-BQ), induced cell cycle arrest at the G1 phase accompanied with decreased expression of Cyclin D1 in a dose-dependently manner. Interestingly, lncRNA-OBFC2A overexpression was found in AHH-1 cells treated with 1,4-BQ and while interference with lncRNA-OBFC2A, the expression of Cyclin D1 were reversed. Further, we found that lncRNA-OBFC2A can interact with Smad3 to control cell cycle via modulating Cyclin D1 expression. In benzene exposed workers, the expression of lncRNA-OBFC2A and Smad3 increased while cyclin D1 decreased which was consistent with the in vitro experiment, meanwhile, the significant associations among them were also found. Thus, these findings indicate that lncRNA-OBFC2A targeted to Smad3 regulated cyclin D1 influences cell cycle arrest induced by 1,4-BQ. LncRNA-OBFC2A, Smad3 and Cyclin D1 as a set of biomarkers play important roles in benzene haematotoxicity.
长期接触苯与白血病等不良健康影响有关。据报道，异常的细胞周期进程参与肿瘤发生。我们之前的研究发现，lncRNA-OBFC2A通过调节细胞增殖参与苯毒性作用。然而，lncRNA-OBFC2A在细胞周期调控中的功能仍不清楚，其确切机制有待探索。体外研究结果表明，苯代谢产物1,4-苯醌（1,4-BQ）以剂量依赖的方式诱导细胞周期阻滞于G1期，同时伴有细胞周期蛋白D1表达降低。有趣的是，在用1,4-BQ处理的AHH-1细胞中发现lncRNA-OBFC2A过表达，而干扰lncRNA-OBFC2A后，细胞周期蛋白D1的表达发生逆转。此外，我们发现lncRNA-OBFC2A可与Smad3相互作用，通过调节细胞周期蛋白D1的表达来控制细胞周期。在接触苯的工人中，lncRNA-OBFC2A和Smad3的表达增加，而细胞周期蛋白D1减少，这与体外实验一致，同时，还发现它们之间存在显著关联。因此，这些发现表明，靶向Smad3的lncRNA-OBFC2A调节细胞周期蛋白D1影响1,4-BQ诱导的细胞周期阻滞。lncRNA-OBFC2A、Smad3和细胞周期蛋白D1作为一组生物标志物在苯血液毒性中起重要作用。
